System and process for retina phototherapy

ABSTRACT

A system and process for treating retinal diseases includes passing a plurality of radiant beams, i.e., laser light beams, through an optical lens or mask to optically shape the beams. The shaped beams are applied to at least a portion of the retina. Due to the selected parameters of the beams—pulse length, power and duty cycle—the beams can be applied to substantially the entire retina, including the fovea, without damaging retinal or foveal tissue, while still attaining the benefits of retinal phototherapy or photostimulation.

BACKGROUND OF THE INVENTION

The present invention generally relates to phototherapy orphotostimulation of biological tissue, such as laser retinalphotocoagulation therapy. More particularly, the present invention isdirected to a system and process for treating retinal diseases anddisorders by using harmless, subthreshold phototherapy orphotostimulation of the retina.

Complications of diabetic retinopathy remain a leading cause of visionloss in people under sixty years of age. Diabetic macular edema is themost common cause of legal blindness in this patient group. Diabetesmellitus, the cause of diabetic retinopathy, and thus diabetic macularedema, is increasing in incidence and prevalence worldwide, becomingepidemic not only in the developed world, but in the developing world aswell. Diabetic retinopathy may begin to appear in persons with Type I(insulin-dependent) diabetes within three to five years of diseaseonset. The prevalence of diabetic retinopathy increases with duration ofdisease. By ten years, 14%-25% of patients will have diabetic macularedema. By twenty years, nearly 100% will have some degree of diabeticretinopathy. Untreated, patients with clinically significant diabeticmacular edema have a 32% three-year risk of potentially disablingmoderate visual loss.

Until the advent of thermal retinal photocoagulation, there wasgenerally no effective treatment for diabetic retinopathy. Usingphotocoagulation to produce photothermal retinal burns as a therapeuticmaneuver was prompted by the observation that the complications ofdiabetic retinopathy were often less severe in eyes with preexistingretinal scarring from other causes. The Early Treatment of DiabeticRetinopathy Study demonstrated the efficacy of argon laser macularphotocoagulation in the treatment of diabetic macular edema.Full-thickness retinal laser burns in the areas of retinal pathologywere created, visible at the time of treatment as white or gray retinallesions (“suprathreshold” retinal photocoagulation). With time, theselesions developed into focal areas of chorioretinal scarring andprogressive atrophy.

With visible endpoint photocoagulation, laser light absorption heatspigmented tissues at the laser site. Heat conduction spreads thistemperature increase from the retinal pigment epithelium and choroid tooverlying non-pigmented and adjacent unexposed tissues. Laser lesionsbecome visible immediately when damaged neural retina overlying thelaser sight loses its transparency and scatters white ophthalmoscopiclight back towards the observer.

There are different exposure thresholds for retinal lesions that arehaemorrhagic, ophthalmoscopically apparent, or angiographicallydemonstrable. A “threshold” lesion is one that is barely visibleophthalmoscopically at treatment time, a “subthreshold” lesion is onethat is not visible at treatment time, and “suprathreshold” lasertherapy is retinal photocoagulation performed to a readily visibleendpoint. Traditional retinal photocoagulation treatment requires avisible endpoint either to produce a “threshold” lesion or a“suprathreshold” lesion so as to be readily visible and tracked. Infact, it has been believed that actual tissue damage and scarring arenecessary in order to create the benefits of the procedure. The gray towhite retinal burns testify to the thermal retinal destruction inherentin conventional threshold and suprathreshold photocoagulation.Photocoagulation has been found to be an effective means of producingretinal scars, and has become the technical standard for macularphotocoagulation for diabetic macular edema for nearly 50 years.

With reference now to FIG. 1, a diagrammatic view of an eye, generallyreferred to by the reference number 10, is shown. When usingphototherapy, the laser light is passed through the patient's cornea 12,pupil 14, and lens 16 and directed onto the retina 18. The retina 18 isa thin tissue layer which captures light and transforms it into theelectrical signals for the brain. It has many blood vessels, such asthose referred to by reference number 20, to nourish it. Various retinaldiseases and disorders, and particularly vascular retinal diseases suchas diabetic retinopathy, are treated using conventional thermal retinalphotocoagulation, as discussed above. The fovea/macula region, referredto by the reference number 22 in FIG. 1, is a portion of the eye usedfor color vision and fine detail vision. The fovea is at the center ofthe macula, where the concentration of the cells needed for centralvision is the highest. Although it is this area where diseases such asage-related macular degeneration are so damaging, this is the area whereconventional photocoagulation phototherapy cannot be used as damagingthe cells in the foveal area can significantly damage the patient'svision. Thus, with current convention photocoagulation therapies, thefoveal region is avoided.

That iatrogenic retinal damage is necessary for effective lasertreatment of retinal vascular disease has been universally accepted foralmost five decades, and remains the prevailing notion. Althoughproviding a clear advantage compared to no treatment, current retinalphotocoagulation treatments, which produce visible gray to white retinalburns and scarring, have disadvantages and drawbacks. Conventionalphotocoagulation is often painful. Local anesthesia, with its ownattendant risks, may be required. Alternatively, treatment may bedivided into stages over an extended period of time to minimizetreatment pain and post-operative inflammation. Transient reduction invisual acuity is common following conventional photocoagulation.

In fact, thermal tissue damage may be the sole source of the manypotential complications of conventional photocoagulation which may leadto immediate and late visual loss. Such complications includeinadvertent foveal burns, pre- and sub-retinal fibrosis, choroidalneovascularization, and progressive expansion of laser scars.Inflammation resulting from the tissue destruction may cause orexacerbate macular edema, induced precipitous contraction offibrovascular proliferation with retinal detachment and vitreoushemorrhage, and cause uveitis, serous choroidal detachment, angleclosure or hypotony. Some of these complications are rare, while others,including treatment pain, progressive scar expansion, visual field loss,transient visual loss and decreased night vision are so common as to beaccepted as inevitable side-effects of conventional laser retinalphotocoagulation. In fact, due to the retinal damage inherent inconventional photocoagulation treatment, it has been limited in densityand in proximity to the fovea, where the most visually disablingdiabetic macular edema occurs.

Notwithstanding the risks and drawbacks, retinal photocoagulationtreatment, typically using a visible laser light, is the currentstandard of care for proliferative diabetic retinopathy, as well asother retinopathy and retinal diseases, including diabetic macular edemaand retinal venous occlusive diseases which also respond well to retinalphotocoagulation treatment. In fact, retinal photocoagulation is thecurrent standard of care for many retinal diseases, including diabeticretinopathy.

Another problem is that the treatment requires the application of alarge number of laser doses to the retina, which can be tedious andtime-consuming. Typically, such treatments call for the application ofeach dose in the form of a laser beam spot applied to the target tissuefor a predetermined amount of time, from a few hundred milliseconds toseveral seconds. Typically, the laser spots range from 50-500 microns indiameter. Their laser wavelength may be green, yellow, red or eveninfrared. It is not uncommon for hundreds or even in excess of onethousand laser spots to be necessary in order to fully treat the retina.The physician is responsible for insuring that each laser beam spot isproperly positioned away from sensitive areas of the eye, such as thefovea, that could result in permanent damage. Laying down a uniformpattern is difficult and the pattern is typically more random thangeometric in distribution. Point-by-point treatment of a large number oflocations tends to be a lengthy procedure, which frequently results inphysician fatigue and patient discomfort.

U.S. Pat. No. 6,066,128, to Bahmanyar describes a method of multi-spotlaser application, in the form of retinal-destructive laserphotocoagulation, achieved by means of distribution of laser irradiationthrough an array of multiple separate fiber optic channels and microlenses. While overcoming the disadvantages of a point-by-point laserspot procedure, this method also has drawbacks. However, a limitation ofthe Bahmanyar method is differential degradation or breakage of thefiber optics or losses due to splitting the laser source into multiplefibers, which can lead to uneven, inefficient and/or suboptimal energyapplication. Another limitation is the constraint on the size anddensity of the individual laser spots inherent in the use of an opticalsystem of light transmission fibers in micro lens systems. Themechanical constraint of dealing with fiber bundles can also lead tolimitations and difficulties focusing and aiming the multi-spot array.

U.S. Patent Publication 2010/0152716 A1 to Previn describes a differentsystem to apply destructive laser irradiation to the retina using alarge retinal laser spot with a speckle pattern, oscillated at a highfrequency to homogenize the laser irradiance throughout the spot.However, a problem with this method is the uneven heat buildup, withhigher tissue temperatures likely to occur toward the center of thelarge spot. This is aggravated by uneven heat dissipation by the ocularcirculation resulting in more efficient cooling towards the margins ofthe large spot compared to the center. That is, the speckle patternbeing oscillated at a high frequency can cause the laser spots to beoverlapping or so close to one another that heat builds up andundesirable tissue damage occurs. Previn's speckle technique achievesaveraging of point laser exposure within the larger exposure via therandom fluctuations of the speckle pattern. However, such averagingresults from some point exposures being more intense than others,whereas some areas within the exposure area may end with insufficientlaser exposure, whereas other areas will receive excessive laserexposure. In fact, Previn specifically notes the risk of excessiveexposure or exposure of sensitive areas, such as the fovea, which shouldbe avoided with this system. Although these excessively exposed spotsmay result in retinal damage, Previn's invention is explicitly intendedto apply damaging retinal photocoagulation to the retina, other than thesensitive area such as the fovea.

However, all conventional retinal photocoagulation treatments, includingthose described by Previn and Bahmanyar, create visible endpoint laserphotocoagulation in the form of gray to white retinal burns and lesions,as discussed above. Recently, the inventor has discovered thatsubthreshold photocoagulation in which no visible tissue damage or laserlesions were detectable by any known means including ophthalmoscopy;infrared, color, red-free or autofluorescence fundus photography instandard or retro-mode; intravenous fundus fluorescein or indocyaninegreen angiographically, or Spectral-domain optical coherence tomographyat the time of treatment or any time thereafter has produced similarbeneficial results and treatment without many of the drawbacks andcomplications resulting from conventional visible threshold andsuprathreshold photocoagulation treatments. It has been determined thatwith the proper operating parameters, subthreshold photocoagulationtreatment can be, and may ideally be, applied to the entire retina,including sensitive areas such as the fovea, without visible tissuedamage or the resulting drawbacks or complications of conventionalvisible retinal photocoagulation treatments. Moreover, by desiring totreat the entire retina, or confluently treat portions of the retina,laborious and time-consuming point-by-point laser spot therapy can beavoided. In addition, the inefficiencies and inaccuracies inherent toinvisible endpoint laser treatment resulting in suboptimal tissue targetcoverage can also be avoided.

SUMMARY OF THE INVENTION

The present invention resides in a process and system for treatingretinal diseases and disorders by means of harmless, subthresholdphotocoagulation phototherapy. Although the present invention isparticularly useful in treating diabetic retinopathy, including diabeticmacular edema, it will be understood that the present invention alsoapplies to all other retinal conditions, including but not limited toretinal venous occlusive diseases and idiopathic central serouschorioretinopathy, proliferative diabetic retinopathy, and retinalmacroaneurysm as reported, which respond well to traditional retinalphotocoagulation treatments; but having potential application aspreventative and rejuvenative in disorders such as genetic diseases andage-related macular degeneration and others.

The present invention is directed a process for performing retinalphototherapy or photostimulation. The process includes generating aplurality of radiant beams, such as micropulsed laser light beams,passing the beams through an optical lens or mask to optically shape thebeams, and applying the beams to at least a portion of the retina,possibly including at least a portion of the fovea. Each beam has apredetermined wavelength, power, and duty cycle.

The process may include coupling the beams into a single output beambefore performing the passing or applying steps. The passing andapplying steps are then performed using the single output beam. Theapplying step includes steering the single output beam according to anoffset pattern configured to achieve complete coverage of the retina forthe wavelength of a selected beam of the plurality of beams. Thesteering step also includes steering the single output beam according tothe offset pattern so as to achieve incomplete or overlapping coverageof the retina for the wavelengths of non-selected beams.

Alternatively, the applying step may involve sequentially applying eachof the radiant beams to at least a portion of the retina. In this case,the applying step involves steering each of the radiant beams accordingto an offset pattern configured to achieve complete coverage of theretina for each wavelength of each of the radiant beams. The steeringstep also includes steering each of the radiant beams according to theoffset pattern so as to result in identical coverage of the retina foreach wavelength and exclude simultaneous treatment of the retina bymultiple radiant beams.

The passing step may include separately passing each of the radiantbeams through separate optical lenses or masks for each radiant beam.Each of the separate optical lenses or masks is configured so as tooptically shape each radiant beam according to its wavelength so as toproduce each beam in a single predetermined pattern. In this case, thesingle predetermined pattern is the same for each beam. The opticallyshaped beams are combined into a single beam of multiple wavelengthshaving a single predetermined pattern. The single beam of multiplewavelengths is steered according to an offset pattern configured toachieve complete coverage of the retina for the single predeterminedpattern.

The process for performing retinal phototherapy or photostimulation mayalso involve generating a radiant beam, passing the beam through anoptical lens or mask to optically shape the beam, directing the beamthrough an aperture configured to selectively transmit or block thebeam, and applying the beam to at least a portion of the retina,including at least a portion of the fovea, according to theconfiguration of the aperture. The beam has a predetermined wavelength,power, and duty cycle.

The optical lens or mask may include diffractive optics to generate aplurality of spots from the beams. Similarly, the optical lens or maskmay include a plurality of fiber optic wires to generate the pluralityof spots. A person of ordinary skill in the art will understand thatafter a beam is passed through diffractive optics or other device forgenerating spots, the beam comprises a plurality of spots. Thus, theapplying step, while stating that it is applying a beam to the retina,that beam is made up of a plurality of spots resulting from thediffraction and not a single continuous beam. The remainder of thisdescription will refer to the applying step as applying beams, whereineach beam comprises a plurality of spots to the extent the beam waspassed through diffractive optics. The applying step includes applyingthe plurality of beams to at least a portion of the retina.

The aperture may be included in the process using a single beam orplurality of beams. The aperture may comprise an iris aperture or a gridaperture. Either process may include adjusting a diaphragm on the irisaperture so as to block the radiant beams from an outer perimeterportion of the retina and transmit the radiant beam to an inner centralportion of the retina.

Alternatively, a liquid crystal display array on the grid aperture maybe configured so as to block the radiant beams from one or moreselective grid portions of the retina and transmit the radiant beams toany unblocked portions of the retina. The grid aperture may be used toselectively block the beam/beams so as to attenuate areas of peak poweror to prevent treatment of scar tissue on the retina. The aperture mayalso be used to selectively transmit the beam/beams to disease markerson the retina.

The process may also include the step of displaying a fundus image ofthe patient's retina parallel to or superimposed over a result imagefrom a retinal diagnostic modality. This parallel or superimposeddisplay may facilitate determination of areas to block or not blockduring the applying step.

The process may also include the step of archiving a fundus image of theretina before, during and/or after the applying step. One may alsorecording treatment parameters of the applying step, includinggraphically noting areas of treatment application or treatmentexclusion.

In accordance with the present invention, a system for treating retinaldiseases and disorders comprises a laser producing a radiant beam. In aparticularly preferred embodiment, the radiant beam is a light beamhaving an infrared wavelength, such as between 750 nm-1300 nm, andpreferably approximately 810 nm. The light beam has an intensity ofbetween 100-590 watts per square centimeter, and preferablyapproximately 350 watts per square centimeter. The exposure envelope ofthe laser is generally 500 milliseconds or less. The laser has a dutycycle of less than 10%, and typically approximately 5% or less. Themicropulse frequency is preferably 500 Hz.

An optical lens or mask optically shapes the light beam from the laserinto a geometric object or pattern. For example, the optical lens ormask, such as a diffraction grating or plurality of fiber optics,produces a simultaneous pattern of spaced apart laser spots.

An optical scanning mechanism controllably directs the light beam objector pattern onto the retina. The light beam geometric object or patternis incrementally moved a sufficient distance from where the light beamwas previously applied to the retina, to avoid tissue damage, prior toreapplying the light beam to the retina.

The light beam is applied to at least a portion of the retina, such asat eighteen to fifty-five times the American National StandardsInstitute (ANSI) maximum permissible exposure (MPE) level. Given theparameters of the generated laser light beam, including the pulselength, power, and duty cycle, no visible laser lesions or tissue damageis detectable ophthalmoscopically or angiographically or to anycurrently known means after treatment, allowing the entire retina,including the fovea, to be treated without damaging retinal or fovealtissue while still providing the benefits of photocoagulation treatment.

Other features and advantages of the present invention will becomeapparent from the following more detailed description, taken inconjunction with the accompanying drawings, which illustrate, by way ofexample, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate the invention. In such drawings:

FIG. 1 is a cross-sectional diagrammatic view of a human eye;

FIGS. 2A-2F are graphic representations of the effective surface area ofvarious modes of retinal laser treatment;

FIG. 3 is a diagrammatic view illustrating a system used for treating aretinal disease or disorder in accordance with the present invention;

FIG. 4 is a diagrammatic view of an exemplary optical lens or mask usedto generate a geometric pattern, in accordance with the presentinvention;

FIG. 5 is a top plan view of an optical scanning mechanism, used inaccordance with the present invention;

FIG. 6 is a partially exploded view of the optical scanning mechanism ofFIG. 5, illustrating the various component parts thereof;

FIG. 7 illustrates controlled offset of exposure of an exemplarygeometric pattern grid of laser spots to treat the retina in accordancewith the present invention;

FIG. 8 is a diagrammatic view illustrating the units of a geometricobject in the form of a line controllably scanned to treat an area ofthe retina in accordance with the present invention;

FIG. 9 is a diagrammatic view similar to FIG. 8, but illustrating thegeometric line or bar rotated to treat an area of the retina;

FIG. 10 is an illustration of a cross-sectional view of a diseased humanretina before treatment with the present invention;

FIG. 11 is a cross-sectional view similar to FIG. 10, illustrating theportion of the retina after treatment using the present invention;

FIG. 12 is a diagrammatic view illustrating an alternate embodiment of asystem used for treating a retinal disease or disorder in accordancewith the present invention;

FIG. 13 is a diagrammatic view illustrating yet another alternateembodiment of a system used for treating a retinal disease or disorderin accordance with the present invention;

FIG. 14 is a front view of a camera including an iris aperture of thepresent invention; and

FIG. 15 is a front view of a camera including an LCD aperture of thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to a system and process for treatingretinal diseases, including vascular retinal diseases such as diabeticretinopathy and diabetic macular edema, by means of predeterminedparameters producing harmless, true subthreshold photocoagulation. Theinventor's finding that retinal laser treatment that does not cause anylaser-induced retinal damage, but can be at least as effective asconventional retinal photocoagulation is contrary to conventionalthinking and practice.

Conventional thinking assumes that the physician must intentionallycreate retinal damage as a prerequisite to therapeutically effectivetreatment. With reference to FIG. 2, FIGS. 2A-2F are graphicrepresentations of the effective surface area of various modes ofretinal laser treatment for retinal vascular disease. The graybackground represents the retina 30 which is unaffected by the lasertreatment. The black areas 32 are areas of the retina which aredestroyed by conventional laser techniques. The lighter gray or whiteareas 34 represent the areas of the retina affected by the laser, butnot destroyed.

FIG. 2A illustrates the therapeutic effect of conventional argon laserretinal photocoagulation. The therapeutic effects attributed tolaser-induced thermal retinal destruction include reduced metabolicdemand, debulking of diseased retina, increased intraocular oxygentension and ultra production of vasoactive cytokines, including vascularendothelial growth factor (VEGF).

With reference to FIG. 2B, increasing the burn intensity of thetraditional laser burn is shown. It will be seen that the burned anddamaged tissue area 32 is larger, which has resulted in a larger “haloeffect” of heated, but undamaged, surrounding tissue 34. Laboratorystudies have shown that increased burn intensity is associated with anenhanced therapeutic effect, but hampered by increased loss offunctional retina and inflammation. However, with reference to FIG. 2C,when the intensity of the conventional argon laser photocoagulation isreduced, the area of the retina 34 affected by the laser but notdestroyed is also reduced, which may explain the inferior clinicalresults from lower-intensity/lower-density or “mild” argon laser gridphotocoagulation compared to higher-intensity/higher-density treatment,as illustrated in FIG. 2B.

With reference to FIG. 2D, it has been found that low-fluencephotocoagulation with short-pulse continuous wave laserphotocoagulation, also known as selective retinal therapy, producesminimal optical and lateral spread of laser photothermal tissue effects,to the extent that the area of the retina affected by the laser but notdestroyed is minimal to nonexistent. Thus, despite damage or completeablation of the directly treated retina 30, the rim of thetherapeutically affected and surviving tissue is scant or absent. Thisexplains the recent reports finding superiority of conventional argonlaser photocoagulation over PASCAL for diabetic retinopathy.

However, the inventor has shown that such thermal retinal damage isunnecessary and questioned whether it accounts for the benefits of theconventional laser treatments. Instead, the inventor has surmised thatthe therapeutic alterations in the retinal pigment epithelium (RPE)cytokine production elicited by conventional photocoagulation comes fromcells at the margins of traditional laser burns, affected but not killedby the laser exposure, referred to by the reference number 34 in FIG. 2.

FIG. 2E represents the use of a low-intensity and low-density laser,such as a micropulsed diode laser. This creates subthreshold retinalphotocoagulation, shown by the reference number 34, without any visibleburn areas 32. All areas of the retinal pigment epithelium exposed tothe laser irradiation are preserved, and available to contributetherapeutically.

The subthreshold retinal photocoagulation is defined as retinal laserapplications biomicroscopically invisible at the time of treatment.Unfortunately, the term has often been used in the art to describeseveral different clinical scenarios reflecting widely varying degreesof laser-induced thermal retinal damage. The use of the term“subthreshold” falls into three categories reflecting common usage andthe historical and morphological evolution of reduced-intensityphotocoagulation for retinal vascular disease toward truly invisiblephototherapy which the invention embodies.

“Classical subthreshold” for photocoagulation describes the earlyattempts at laser intensity reduction using conventional continuousargon, krypton, and diode lasers. Although the retinal burns werenotably less obvious than the conventional “threshold” (photocoagulationconfined to the outer retina and thus less visible at time of treatment)or even milder “suprathreshold” (full-thickness retinal photocoagulationgenerally easily visible at the time of treatment), the lesions of“classical” subthreshold photocoagulation were uniformly visible bothclinically and by fundus fluorescein angiography (FFA) at the time oftreatment and thereafter.

“Clinical subthreshold” photocoagulation describes the next epiphany ofevolution of laser-induced retinal damage reduction, describing alower-intensity but persistently damaging retinal photocoagulation usingeither a micropulsed laser or short-pulsed continuous wave laser thatbetter confine the damage to the outer retina and retinal pigmentationepithelium. In “clinical” subthreshold photocoagulation, the laserlesions may in fact be ophthalmoscopically invisible at the time oftreatment, however, as laser-induced retinal damage remains the intendedpoint of treatment, laser lesions are produced which generally becomeincreasingly clinically visible with time, and many, if not all, laserlesions can be seen by FFA, fundus autofluorescence photography (FAF),and/or spectral-domain (SD) optical coherence tomography (OCT) at thetime of treatment and thereafter.

“True” subthreshold photocoagulation, as a result of the presentinvention, is invisible and includes laser treatment non-discernible byany other known means such as FFA, FAF, or even SD-OCT. “Truesubthreshold” photocoagulation is therefore defined as a laser treatmentwhich produces absolutely no retinal damage detectable by any means atthe time of treatment or any time thereafter by known means ofdetection. As such, with the absence of lesions and other tissue damageand destruction, FIGS. 2E and 2F represent the result of “true”,invisible subthreshold photocoagulation.

Various parameters have been determined to achieve “true” subthresholdor “low-intensity” effective photocoagulation. These include providingsufficient power to produce effective treatment retinal laser exposure,but not too high to create tissue damage or destruction. Truesubthreshold laser applications can be applied singly or to create ageometric object or pattern of any size and configuration to minimizeheat accumulation, but assure uniform heat distribution as well asmaximizing heat dissipation such as by using a low duty cycle. Theinventor has discovered how to achieve therapeutically effective andharmless true subthreshold retinal laser treatment. The inventor hasalso discovered that placement of true subthreshold laser applicationsconfluently and contiguously to the retinal surface improves andmaximizes the therapeutic benefits of treatment without harm or retinaldamage.

The American Standards Institute (ANSI) has developed standards for safeworkplace laser exposure based on the combination of theoretical andempirical data. The “maximum permissible exposure” (MPE) is the safetylevel, set at approximately 1/10^(th) of the laser exposure levelexpected to produce biological effects. At a laser exposure level of 1times MPE, absolute safety would be expected and retinal exposure tolaser radiation at this level would be expected to have no biologicaffect. Based on ANSI data, a 50% of some risk of suffering a barelyvisible (threshold) retinal burn is generally encountered at 10 timesMPE for conventional continuous wave laser exposure. For a low-dutycycle micropulsed laser exposure of the same power, the risk ofthreshold retinal burn is approximately 100 times MPE. Thus, thetherapeutic range—the interval of doing nothing at all and the 50% ofsome likelihood of producing a threshold retinal burn—for low-duty cyclemicropulsed laser irradiation is 10 times wider than for continuous wavelaser irradiation with the same energy. It has been determined that safeand effective subthreshold photocoagulation using a low-duty cyclemicropulsed diode laser is between 18 times and 55 times MPE, such aswith a preferred laser exposure to the retina at 47 times MPE for anear-infrared 810 nm diode laser. At this level, the inventor hasobserved that there is therapeutic effectiveness with no retinal damagewhatsoever.

It has been found that the intensity or power of a low-duty cycle 810 nmlaser beam between 100 watts to 590 watts per square centimeter iseffective yet safe. A particularly preferred intensity or power of thelaser light beam is approximately 250-350 watts per square centimeterfor an 810 nm micropulsed diode laser.

Power limitations in current micropulsed diode lasers require fairlylong exposure duration. The longer the laser exposure, the moreimportant the center-spot heat dissipating ability toward the unexposedtissue at the margins of the laser spot and toward the underlyingchoriocapillaris. Thus, the radiant beam of an 810 nm diode laser shouldhave an exposure envelope duration of 500 milliseconds or less, andpreferably approximately 100-300 milliseconds. Of course, if micropulseddiode lasers become more powerful, the exposure duration will belessened accordingly.

Another parameter of the present invention is the duty cycle (thefrequency of the train of micropulses, or the length of the thermalrelaxation time in between consecutive pulses). It has been found thatthe use of a 10% duty cycle or higher adjusted to deliver micropulsedlaser at similar irradiance at similar MPE levels significantly increasethe risk of lethal cell injury, particularly in darker fundi. However,duty cycles less than 10%, and preferably approximately 5% duty cycle(or less) demonstrated adequate thermal rise and treatment at the levelof the RPE cell to stimulate a biologic response, but remained below thelevel expected to produce lethal cell injury, even in darkly pigmentedfundi. Moreover, if the duty cycle is less than 5%, the exposureenvelope duration in some instances can exceed 500 milliseconds.

In a particularly preferred embodiment, the use of small retinal laserspots is used. This is due to the fact that larger spots can contributeto uneven heat distribution and insufficient heat dissipation within thelarge retinal laser spot, potentially causing tissue damage or eventissue destruction towards the center of the larger laser spot. In thisusage, “small” would generally apply to retinal spots less than 3 mm indiameter. However, the smaller the retinal spot, the more ideal the heatdissipation and uniform energy application becomes. Thus, at the powerintensity and exposure duration described above, small spots, such as25-300 micrometers in diameter, or small geometric lines or otherobjects are preferred so as to maximize even heat distribution and heatdissipation to avoid tissue damage.

Thus, the following key parameters have been found in order to createharmless, “true” subthreshold photocoagulation in accordance with thepresent invention: a) a low (preferably 5% or less) duty cycle; b) asmall spot size to minimize heat accumulation and assure uniform heatdistribution within a given laser spot so as to maximize heatdissipation; c) sufficient power to produce retinal laser exposures ofbetween 18 times-55 times MPE producing an RPE temperature rise of 7°C.-14° C.; and retinal irradiance of between 100-590 W/cm².

Using the foregoing parameters, a harmless, “true” subthresholdphotocoagulation phototherapy treatment can be attained which has beenfound to produce the benefits of conventional photocoagulationphototherapy, but avoid the drawbacks and complications of conventionalphototherapy. In fact, “true” subthreshold photocoagulation phototherapyin accordance with the present invention enables the physician to applya “low-intensity/high-density” phototherapy treatment, such asillustrated in FIG. 2F, and treat the entire retina, including sensitiveareas such as the macula and even the fovea without creating visual lossor other damage. As indicated above, using conventional phototherapies,the entire retina, and particularly the fovea, cannot be treated as itwill create vision loss due to the tissue damage in sensitive areas.

Conventional retina-damaging laser treatment is limited in treatmentdensity, requiring subtotal treatment of the retina, including subtotaltreatment of the particular areas of retinal abnormality. However,recent studies demonstrate that eyes in diabetics may have diffuseretinal abnormalities without otherwise clinically visible diabeticretinopathy, and eyes with localized areas of clinically identifiableabnormality, such as diabetic macular edema or central serouschorioretinopathy, often have total retinal dysfunction detectable onlyby retinal function testing. The ability of the invention to harmlesslytreat the entire retina thus allows, for the first time, bothpreventative and therapeutic treatment of eyes with retinal diseasecompletely rather than locally or subtotally; and early treatment priorto the manifestation of clinical retinal disease and visual loss.

As discussed above, it is conventional thinking that tissue damage andlesions must be created in order to have a therapeutic effect. However,the inventor has found that this simply is not the case. In the absenceof laser-induced retinal damage, there is no loss of functional retinaltissue and no inflammatory response to treatment. Adverse treatmenteffects are thus completely eliminated and functional retina preservedrather than sacrificed. This may yield superior visual acuity resultscompared to conventional photocoagulation treatment.

The present invention spares the neurosensory retina and is selectivelyabsorbed by the RPE. Current theories of the pathogenesis of retinalvascular disease especially implicate cytokines, potent extra cellularvasoactive factors produced by the RPE, as important mediators ofretinal vascular disease. The present invention both selectively targetsand avoids lethal buildup within RPE. Thus, with the present inventionthe capacity for the treated RPE to participate in a therapeuticresponse is preserved and even enhanced rather than eliminated as aresult their destruction of the RPE in conventional photocoagulationtherapies.

It has been noted that the clinical effects of cytokines may follow a“U-shaped curve” where small physiologic changes in cytokine production,denoted by the left side of curve, may have large clinical effectscomparable to high-dose (pharmacologic) therapy (denoted by the rightside of the curve). Using sublethal laser exposures in accordance withthe present invention may be working on the left side of the curve wherethe treatment response may approximate more of an “on/off” phenomenonrather than a dose-response. This might explain the clinicaleffectiveness of the present invention observed at low reportedirradiances. This is also consistent with clinical experience andin-vitro studies of laser-tissue interaction, wherein increasingirradiance may simply increase the risk of thermal retinal damagewithout improving the therapeutic effect.

With reference again to FIG. 2, the invisible, true subthresholdphotocoagulation phototherapy maximizes the therapeutic recruitment ofthe RPE through the concept of “maximize the affected surface area”, inthat all areas of RPE exposed to the laser irradiation are preserved,and available to contribute therapeutically. As discussed above withrespect to FIG. 2, it is believed that conventional therapy creates atherapeutic ring around the burned or damaged tissue areas, whereas thepresent invention creates a therapeutic area without any burned orotherwise destroyed tissue.

In another departure from conventional retinal photocoagulation, a lowred to infrared laser light beam, such as from an 810 nm micropulseddiode laser, is used instead of an argon laser. It has been found thatthe 810 nm diode laser is minimally absorbed and negligibly scattered byintraretinal blood, cataract, vitreous hemorrhage and even severelyedematous neurosensory retina. Differences in fundus coloration resultprimarily from differences in choroid pigmentation, and less ofvariation of the target RPE. Treatment in accordance with the presentinvention is thus simplified, requiring no adjustment in laserparameters for variations in macular thickening, intraretinalhemorrhage, and media opacity such as cataracts or fundus pigmentation,reducing the risk of error.

However, it is contemplated that the present invention could be utilizedwith micropulsed emissions of other wavelengths, such as the recentlyavailable 577 nm yellow and 532 nm green lasers, and others. The higherenergies and different tissue absorption characteristic of shorterwavelength lasers may increase retinal burn risk, effectively narrowingthe therapeutic window. In addition, the shorter wavelengths are morescattered by opaque ocular media, retinal hemorrhage and macular edema,potentially limiting usefulness and increasing the risk of retinaldamage in certain clinical settings. Thus, a low red to infrared laserlight beam is still preferred.

In fact, low power red and near-infrared laser exposure is known topositively affect many cell types, particularly normalizing the behaviorof cells and pathological environments, such as diabetes, through avariety of intracellular photo-acceptors. Cell function, in cytokineexpression, is normalized and inflammation reduced. By normalizingfunction of the viable RPE cells, the invention may induce changes inthe expression of multiple factors physiologically as opposed to drugtherapy that typically narrowly targets only a few post-cellular factorspharmacologically. The laser-induced physiologic alteration of RPEcytokine expression may account for the slower onset but long lastingbenefits using the present invention. Furthermore, use of aphysiologically invisible infrared or near-infrared laser wavelength isperceived as comfortable by the patient, and does not cause reactivepupillary constriction, allowing visualization of the ocular fundus andtreatment of the retina to be performed without pharmacologic dilationof the patient pupil. This also eliminates the temporary of visualdisability typically lasting many hours following pharmacologicpupillary dilation currently required for treatment with conventionallaser photocoagulation. Currently, patient eye movement is a concern notonly for creating the pattern of laser spots to treat the intended area,but also could result in exposure of conventional therapy to sensitiveareas of the eye, such as the fovea, resulting in loss of vision orother complications.

With reference now to FIG. 3, a schematic diagram is shown of a systemfor realizing the process of the present invention. The system,generally referred to by the reference number 40, includes a laserconsole 42, such as for example the 810 nm near infrared micropulseddiode laser in the preferred embodiment. The laser generates a laserlight beam which is passed through an optical lens or mask, or aplurality of optical lenses and/or masks 44 as needed. The laserprojector optics 44 pass the shaped light beam to a coaxial wide-fieldnon-contact digital optical viewing system/camera 46 for projecting thelaser beam light onto the eye 48 of the patient. It will be understoodthat the box labeled 46 can represent both the laser beam projector aswell as a viewing system/camera, which might in reality comprise twodifferent components in use. The viewing system/camera 46 providesfeedback to a display monitor 50, which may also include the necessarycomputerized hardware, data input and controls, etc. for manipulatingthe laser 42, the optics 44, and/or the projection/viewing components46.

As discussed above, current treatment requires the application of alarge number of individual laser beam spots applied to the target tissueto be treated. These can number in the hundreds or even thousands forthe desired treatment area. This is very time intensive and laborious.

With reference now to FIG. 4, in one embodiment, the laser light beam 52is passed through a collimator lens 54 and then through a mask 56. In aparticularly preferred embodiment, the mask 56 comprises a diffractiongrating. The mask/diffraction grating 56 produces a geometric object, ormore typically a geometric pattern of simultaneously produced multiplelaser spots or other geometric objects. This is represented by themultiple laser light beams labeled with reference number 58.Alternatively, the multiple laser spots may be generated by a pluralityof fiber optic wires. Either method of generating laser spots allows forthe creation of a very large number of laser spots simultaneously over avery wide treatment field, such as consisting of the entire retina. Infact, a very high number of laser spots, perhaps numbering in thehundreds even thousands or more could cover the entire ocular fundus andentire retina, including the macula and fovea, retinal blood vessels andoptic nerve. The intent of the process in the present invention is tobetter ensure complete and total coverage and treatment, sparing none ofthe retina by the laser so as to improve vision.

Using optical features with a feature size on par with the wavelength ofthe laser employed, for example using a diffraction grating, it ispossible to take advantage of quantum mechanical effects which permitssimultaneous application of a very large number of laser spots for avery large target area. The individual spots produced by suchdiffraction gratings are all of a similar optical geometry to the inputbeam, with minimal power variation for each spot. The result is aplurality of laser spots with adequate irradiance to produce harmlessyet effective treatment application, simultaneously over a large targetarea. The present invention also contemplates the use of other geometricobjects and patterns generated by other diffractive optical elements.

The laser light passing through the mask 56 diffracts, producing aperiodic pattern a distance away from the mask 56, shown by the laserbeams labeled 58 in FIG. 4. The single laser beam 52 has thus beenformed into hundreds or even thousands of individual laser beams 58 soas to create the desired pattern of spots or other geometric objects.These laser beams 58 may be passed through additional lenses,collimators, etc. 60 and 62 in order to convey the laser beams and formthe desired pattern on the patient's retina. Such additional lenses,collimators, etc. 60 and 62 can further transform and redirect the laserbeams 58 as needed.

Arbitrary patterns can be constructed by controlling the shape, spacingand pattern of the optical mask 56. The pattern and exposure spots canbe created and modified arbitrarily as desired according to applicationrequirements by experts in the field of optical engineering.Photolithographic techniques, especially those developed in the field ofsemiconductor manufacturing, can be used to create the simultaneousgeometric pattern of spots or other objects.

Typically, the system of the present invention incorporates a guidancesystem to ensure complete and total retinal treatment with retinalphotostimulation. As the treatment method of the present invention isharmless, the entire retina, including the fovea and even optical nerve,can be treated. Moreover, protection against accidental visual loss byaccidental patient movement is not a concern. Instead, patient movementwould mainly affect the guidance in tracking of the application of thelaser light to ensure adequate coverage. Fixation/tracking/registrationsystems consisting of a fixation target, tracking mechanism, and linkedto system operation are common in many ophthalmic diagnostic systems andcan be incorporated into the present invention.

With reference now to FIGS. 5 and 6, in a particularly preferredembodiment, the geometric pattern of simultaneous laser spots issequentially offset so as to achieve confluent and complete treatment ofthe retinal surface. Although a segment of the retina can be treated inaccordance with the present invention, more ideally the entire retinawill be treated with one treatment. This is done in a time-saving mannerby placing hundreds to thousands of spots over the entire ocular fundusat once. This pattern of simultaneous spots is scanned, shifted, orredirected as an entire array sequentially, so as to cover the entireretina.

This can be done in a controlled manner using an optical scanningmechanism 64 such as that illustrated in FIGS. 5 and 6. FIGS. 5 and 6illustrate an optical scanning mechanism 64 in the form of a MEMSmirror, having a base 66 with electronically actuated controllers 68 and70 which serve to tilt and pan the mirror 72 as electricity is appliedand removed thereto. Applying electricity to the controller 68 and 70causes the mirror 72 to move, and thus the simultaneous pattern of laserspots or other geometric objects reflected thereon to move accordinglyon the retina of the patient. This can be done, for example, in anautomated fashion using electronic software program to adjust theoptical scanning mechanism 64 until complete coverage of the retina, orat least the portion of the retina desired to be treated, is exposed tothe phototherapy. The optical scanning mechanism may also be a smallbeam diameter scanning galvo mirror system, or similar system, such asthat

distributed by Thorlabs. Such a system is capable of scanning the lasersin the desired offsetting pattern.

Since the parameters of the present invention dictate that the appliedradiant energy or laser light is not destructive or damaging, thegeometric pattern of laser spots, for example, can be overlapped withoutcreating any damage. However, in a particularly preferred embodiment, asillustrated in FIG. 7, the pattern of spots are offset at each exposureso as to create space between the immediately previous exposure to allowheat dissipation and prevent the possibility of heat damage or tissuedestruction. Thus, as illustrated in FIG. 7, the pattern, illustratedfor exemplary purposes as a grid of sixteen spots, is offset eachexposure such that the laser spots occupy a different space thanprevious exposures. It will be understood that this occurs until theentire retina, the preferred methodology, has received phototherapy, oruntil the desired effect is attained. This can be done, for example, byapplying electrostatic torque to a micromachined mirror, as illustratedin FIGS. 5 and 6. By combining the use of small retina laser spotsseparated by exposure free areas, prevents heat accumulation, and gridswith a large number of spots per side, it is possible to atraumaticallyand invisibly treat large target areas with short exposure durations farmore rapidly than is possible with current technologies.

By rapidly and sequentially repeating redirection or offsetting of theentire simultaneously applied grid array of spots or geometric objects,complete coverage of the target, such as a human retina, can be achievedrapidly without thermal tissue injury. This offsetting can be determinedalgorithmically to ensure the fastest treatment time and least risk ofdamage due to thermal tissue, depending on laser parameters and desiredapplication. The following has been modeled using the FraunhofferApproximation. With a mask having a nine by nine square lattice, with anaperture radius 9 μm, an aperture spacing of 600 μm, using a 890 nmwavelength laser, with a mask-lens separation of 75 mm, and secondarymask size of 2.5 mm by 2.5 mm, the following parameters will yield agrid having nineteen spots per side separated by 133 μm with a spot sizeradius of 6 μm. The number of exposures “m” required to treat (coverconfluently with small spot applications) given desired area side-length“A”, given output pattern spots per square side “n”, separation betweenspots “R”, spot radius “r” and desired square side length to treat area“A”, can be given by the following formula:

$m = {\frac{A}{nR}{floor}\mspace{11mu}\left( \frac{R}{2\; r} \right)^{2}}$

With the foregoing setup, one can calculate the number of operations mneeded to treat different field areas of exposure. For example, a 3 mm×3mm area, which is useful for treatments, would require 98 offsettingoperations, requiring a treatment time of approximately thirty seconds.Another example would be a 3 cm×3 cm area, representing the entire humanretinal surface. For such a large treatment area, a much largersecondary mask size of 25 mm by 25 mm could be used, yielding atreatment grid of 190 spots per side separated by 133 μm with a spotsize radius of 6 μm. Since the secondary mask size was increased by thesame factor as the desired treatment area, the number of offsettingoperations of approximately 98, and thus treatment time of approximatelythirty seconds, is constant. These treatment times represent at leastten to thirty times reduction in treatment times compared to currentmethods of sequential individual laser spot applications. Field sizes of3 mm would, for example, allow treatment of the entire human macula in asingle exposure, useful for treatment of common blinding conditions suchas diabetic macular edema and age-related macular degeneration.Performing the entire 98 sequential offsettings would ensure entirecoverage of the macula.

Of course, the number and size of retinal spots produced in asimultaneous pattern array can be easily and highly varied such that thenumber of sequential offsetting operations required to completetreatment can be easily adjusted depending on the therapeuticrequirements of the given application.

Furthermore, by virtue of the small apertures employed in thediffraction grating or mask, quantum mechanical behavior may be observedwhich allows for arbitrary distribution of the laser input energy. Thiswould allow for the generation of any arbitrary geometric shapes orpatterns, such as a plurality of spots in grid pattern, lines, or anyother desired pattern. Other methods of generating geometric shapes orpatterns, such as using multiple fiber optical fibers or microlenses,could also be used in the present invention. Time savings from the useof simultaneous projection of geometric shapes or patterns permits thetreatment fields of novel size, such as the 1.2 cm^2 area to accomplishwhole-retinal treatment, in a clinical setting.

With reference now to FIG. 8, instead of a geometric pattern of smalllaser spots, the present invention contemplates use of other geometricobjects or patterns. For example, a single line 74 of laser light,formed by the continuously or by means of a series of closely spacedspots, can be created. An offsetting optical scanning mechanism can beused to sequentially scan the line over an area, illustrated by thedownward arrow in FIG. 8.

With reference now to FIG. 9, the same geometric object of a line 74 canbe rotated, as illustrated by the arrows, so as to create a circularfield of phototherapy. The potential negative of this approach, however,is that the central area will be repeatedly exposed, and could reachunacceptable temperatures. This could be overcome, however, byincreasing the time between exposures, or creating a gap in the linesuch that the central area is not exposed.

With reference again to FIG. 3, due to the unique characteristics of thepresent invention, allowing a single set of optimized laser parameters,which are not significantly influenced by media opacity, retinalthickening, or fundus pigmentation, a simplified user interface ispermitted. While the operating controls could be presented and functionin many different ways, the system permits a very simplified userinterface that might employ only two control functions. That is, an“activate” button, wherein a single depression of this button while in“standby” would actuate and initiate treatment. A depression of thisbutton during treatment would allow for premature halting of thetreatment, and a return to “standby” mode. The activity of the machinecould be identified and displayed, such as by an LED adjacent to orwithin the button. A second controlled function could be a “field size”knob. A single depression of this button could program the unit toproduce, for example, a 3 mm focal or a “macular” field spot. A seconddepression of this knob could program the unit to produce a 6 mm or“posterior pole” spot. A third depression of this knob could program theunit to produce a “pan retinal” or approximately 160°-220° panoramicretinal spot or coverage area. Manual turning of this knob could producevarious spot field sizes therebetween. Within each field size, thedensity and intensity of treatment would be identical. Variation of thefield size would be produced by optical or mechanical masking orapertures, such as the iris or LCD apertures described below.

Fixation software could monitor the displayed image of the ocularfundus. Prior to initiating treatment of a fundus landmark, such as theoptic nerve, or any part or feature of either eye of the patient(assuming orthophoria), could be marked by the operator on the displayscreen. Treatment could be initiated and the software would monitor thefundus image or any other image-registered to any part of either eye ofthe patient (assuming orthophoria) to ensure adequate fixation. A breakin fixation would automatically interrupt treatment. Treatment wouldautomatically resume toward completion as soon as fixation wasestablished. At the conclusion of treatment, determined by completion ofconfluent delivery of the desired laser energy to the target, the unitwould automatically terminate exposure and default to the “on” or“standby” mode. Due to unique properties of this treatment, fixationinterruption would not cause harm or risk patient injury, but onlyprolong the treatment session.

With reference now to FIGS. 10 and 11, spectral-domain OCT imaging isshown in FIG. 10 of the macular and foveal area of the retina beforetreatment with the present invention. FIG. 11 is of the opticalcoherence tomography (OCT) image of the same macula and fovea aftertreatment using the present invention, using a 131 micrometer retinalspot, 5% duty cycle, 0.3 second pulse duration, 0.9 watt peak powerplaced throughout the area of macular thickening, including the fovea.It will be noted that the enlarged dark area to the left of the foveadepression (representing the pathologic retinal thickening of diabeticmacular edema) is absent, as well as the fact that there is an absenceof any laser-induced retinal damage. Such treatment simply would not beattainable with conventional techniques.

The laser could be projected via a wide field non-contact lens to theocular fundus. Customized direction of the laser fields or particulartarget or area of the ocular fundus other than the central area could beaccomplished by an operator joy stick or eccentric patient gaze. Thelaser delivery optics could be coupled coaxially to a wide fieldnon-contact digital ocular fundus viewing system. The image of theocular fundus produced could be displayed on a video monitor visible tothe laser operator. Maintenance of a clear and focused image of theocular fundus could be facilitated by a joy stick on the camera assemblymanually directed by the operator. Alternatively, addition of a targetregistration and tracking system to the camera software would result ina completely automated treatment system.

A fixation image could be coaxially displayed to the patient tofacilitate ocular alignment. This image would change in shape and size,color, intensity, blink or oscillation rate or other regular orcontinuous modification during treatment to avoid photoreceptorexhaustion, patient fatigue and facilitate good fixation.

The field of photobiology reveals that different biologic effects may beachieved by exposing target tissues to lasers of different wavelengths.The same may also be achieved by consecutively applying multiple lasersof either different or the same wavelength in sequence with variabletime periods of separation and/or with different irradiant energies. Thepresent invention anticipates the use of multiple laser, light orradiant wavelengths (or modes) applied simultaneously or in sequence tomaximize or customize the desired treatment effects. This method alsominimizes potential detrimental effects. The following descriptionidentifies two optical methods of providing simultaneous or sequentialapplication of multiple wavelengths.

FIG. 12 illustrates diagrammatically a system which couples multiplelight sources into the pattern-generating optical subassembly describedabove. Specifically, this system 40′ is similar to the system 40described in FIG. 3 above. The primary differences between the alternatesystem 40′ and the earlier described system 40 is the inclusion of aplurality of laser consoles 42, the outputs of which are each fed into afiber coupler 76. The fiber coupler produces a single output that ispassed into the laser projector optics 44 as described in the earliersystem. The coupling of the plurality of laser consoles 42 into a singleoptical fiber is achieved with a fiber coupler 76 as is known in theart. Other known mechanisms for combining multiple light sources areavailable and may be used to replace the fiber coupler described herein.

In this system 40′ the multiple light sources 42 follow a similar pathas described in the earlier system 40, i.e., collimated, diffracted,recollimated, and directed into the retina with a steering mechanism. Inthis alternate system 40′ the diffractive element must functiondifferently than described earlier depending upon the wavelength oflight passing through, which results in a slightly varying pattern. Thevariation is linear with the wavelength of the light source beingdiffracted. In general, the difference in the diffraction angles issmall enough that the different, overlapping patterns may be directedalong the same optical path through the steering mechanism 46 to theretina 48 for treatment. The slight difference in the diffraction angleswill affect how the steering pattern achieves coverage of the retina.

Since the resulting pattern will vary slightly for each wavelength, asequential offsetting to achieve complete coverage will be different foreach wavelength. This sequential offsetting can be accomplished in twomodes. In the first mode, all wavelengths of light are appliedsimultaneously without identical coverage. An offsetting steeringpattern to achieve complete coverage for one of the multiple wavelengthsis used. Thus, while the light of the selected wavelength achievescomplete coverage of the retina, the application of the otherwavelengths achieves either incomplete or overlapping coverage of theretina. The second mode sequentially applies each light source of avarying wavelength with the proper steering pattern to achieve completecoverage of the retina for that particular wavelength. This modeexcludes the possibility of simultaneous treatment using multiplewavelengths, but allows the optical method to achieve identical coveragefor each wavelength. This avoids either incomplete or overlappingcoverage for any of the optical wavelengths.

These modes may also be mixed and matched. For example, two wavelengthsmay be applied simultaneously with one wavelength achieving completecoverage and the other achieving incomplete or overlapping coverage,followed by a third wavelength applied sequentially and achievingcomplete coverage.

FIG. 13 illustrates diagrammatically yet another alternate embodiment ofthe inventive system 40″. This system 40″ is configured generally thesame as the system 40 depicted in FIG. 3. The main difference resides inthe inclusion of multiple pattern-generating subassembly channels tunedto a specific wavelength of the light source. Multiple laser consoles 42are arranged in parallel with each one leading directly into its ownlaser projector optics 44. The laser projector optics of each channel 80a, 80 b, 80 c comprise a collimator 54, mask or diffraction grating 56and recollimators 60, 62 as described in connection with FIG. 4above—the entire set of optics tuned for the specific wavelengthgenerated by the corresponding laser console 42. The output from eachset of optics 44 is then directed to a beam splitter 78 for combinationwith the other wavelengths. It is known by those skilled in the art thata beam splitter used in reverse can be used to combine multiple beams oflight into a single output.

The combined channel output from the final beam splitter 78 c is thendirected through the camera 46 which applies a steering mechanism toallow for complete coverage of the retina 48.

In this system 40″ the optical elements for each channel are tuned toproduce the exact specified pattern for that channel's wavelength.Consequently, when all channels are combined and properly aligned asingle steering pattern may be used to achieve complete coverage of theretina for all wavelengths.

The system 40″ may use as many channels 80 a, 80 b, 80 c, etc. and beamsplitters 78 a, 78 b, 78 c, etc. as there are wavelengths of light beingused in the treatment.

Implementation of the system 40″ may take advantage of differentsymmetries to reduce the number of alignment constraints. For example,the proposed grid patterns are periodic in two dimensions and steered intwo dimensions to achieve complete coverage. As a result, if thepatterns for each channel are identical as specified, the actual patternof each channel would not need to be aligned for the same steeringpattern to achieve complete coverage for all wavelengths. Each channelwould only need to be aligned optically to achieve an efficientcombination.

In system 40″, each channel begins with a light source 42, which couldbe from an optical fiber as in other embodiments of thepattern-generating subassembly. This light source 42 is directed to theoptical assembly 44 for collimation, diffraction, recollimation anddirected into the beam splitter which combines the channel with the mainoutput.

The invention described herein is generally safe for panretinal and/ortrans-foveal treatment. However, it is possible that a user, i.e.,surgeon, preparing to limit treatment to a particular area of the retinawhere disease markers are located or to prevent treatment in aparticular area with darker pigmentation, such as from scar tissue. Inthis case, the camera 46 may be fitted with an iris aperture 82configured to selectively widen or narrow the opening through which thelight is directed into the eye 48 of the patient. FIG. 14 illustrates anopening 84 on a camera 46 fitted with such an iris aperture 82.Alternatively, the iris aperture 82 may be replaced or supplemented by aliquid crystal display (LCD) 86. The LCD 86 acts as a dynamic apertureby allowing each pixel in the display to either transmit or block thelight passing through it. Such an LCD 86 is depicted in FIG. 15.

Preferably, any one of the inventive systems 40, 40′, 40″ includes adisplay on a user interface with a live image of the retina as seenthrough the camera 46. The user interface may include an overlay of thislive image of the retina to select areas where the treatment light willbe limited or excluded by the iris aperture 82 and/or the LCD 86. Theuser may draw an outline on the live image as on a touch screen and thenselect for either the inside or the outside of that outline to havelimited or excluded coverage.

By way of example, if the user identifies scar tissue on the retina thatshould be excluded from treatment, the user would draw an outline aroundthe scar tissue and then mark the interior of that outline for exclusionfrom the laser treatment. The control system and user interface 50 wouldthen send the proper control signal to the LCD 86 to block the projectedtreatment light through the pixels over the selected scar tissue. TheLCD 86 provides an added benefit of being useful for attenuating regionsof the projected pattern. This feature may be used to limit the peakpower output of certain spots within the pattern. Limiting the peakpower of certain spots in the pattern with the highest power output canbe used to make the treatment power more uniform across the retina.

Although the present invention is particularly suited for treatment ofretinal diseases, such as diabetic retinopathy and macular edema, it iscontemplated that it could be used for other diseases as well. Thesystem and process of the present invention could target the trabecularmesh work as treatment for glaucoma, accomplished by another customizedtreatment field template. It is contemplated by the present inventionthat the system and concepts of the present invention be applied tophototherapy treatment of other tissues, such as, but not limited to,the gastrointestinal or respiratory mucosa, delivered endoscopically,for other purposes.

In addition, the results or images from other retinal diagnosticmodalities, such as OCT, retinal angiography, or autofluoresencephotography, might be displayed in parallel or by superimposition on thedisplay image of the patient's fundus to guide, aid or otherwisefacilitate the treatment. This parallel or superimposition of images canfacilitate identification of disease, injury or scar tissue on theretina.

Although several embodiments have been described in detail for purposesof illustration, various modifications may be made without departingfrom the scope and spirit of the invention. Accordingly, the inventionis not to be limited, except as by the appended claims.

What is claimed is:
 1. A process for performing retinalphotostimulation, comprising the steps of: generating a plurality ofradiant treatment beams from a plurality of micropulsed diode lasers,wherein the plurality of radiant treatment beams comprise individualtreatment beams having different predetermined wavelengths; separatelypassing each of the plurality of radiant treatment beams throughrespective optical lenses to optically shape the treatment beams; andsimultaneously applying the plurality of radiant treatment beams to atleast a portion of the retina so as to effect retinal photostimulationthereof; wherein the plurality of treatment beams have a wavelengthbetween 532 nm and 1300 nm, a duty cycle of less than 10%, an exposureduration of 500 milliseconds or less, and a power or intensity of 100watts to 590 watts per square centimeter, to produce true subthresholdphotocoagulation in the retinal tissue without permanently damaging theretinal tissue.
 2. The process of claim 1, wherein the applying stepcomprises the step of steering the plurality of treatment beamsaccording to an offset pattern configured to achieve complete coverageof the retina.
 3. The process of claim 1, including the step ofconfiguring the separate optical lenses so as to optically shape each ofthe plurality of radiant treatment beams according to its predeterminedwavelength so as to produce each radiant treatment beam in a singlepredetermined pattern.
 4. The process of claim 1, including the step ofselectively transmitting the plurality of radiant treatment beams todisease markers on the retina.
 5. The process of claim 1, furthercomprising the step of displaying a fundus image of the retina on adisplay screen, wherein the fundus image is superimposed over a resultimage from a retinal diagnostic modality.
 6. The process of claim 1,further comprising the steps of: archiving a fundus image of the retinabefore the applying step, and recording treatment parameters of theapplying step, including graphically noting areas of treatmentapplication or treatment exclusion.
 7. The process of claim 1, whereinthe optical lenses includes diffractive optics to generate a pluralityof spaced apart radiant treatment beams that are simultaneously appliedto the retinal tissue.
 8. The process of claim 1, wherein the treatmentbeams are applied to the retinal tissue at less than 100 times an ANSImaximum permissible exposure level.
 9. The process of claim 8, whereinthe treatment beams are applied to the retinal tissue between 18 timesand 55 times the ANSI maximum permissible exposure level.
 10. Theprocess of claim 1, wherein the temperature of the retinal tissue israised by the treatment beams between 7 degrees Celsius and 14 degreesCelsius at least during application of the treatment beams to theretinal tissue.
 11. The process of claim 1, wherein the treatment beamshave a wavelength between 750 nm and 1300 nm, a duty cycle of 5% orless, an exposure duration of between 100 and 300 milliseconds, and apower or intensity of 250 watts to 350 watts per square centimeter. 12.The process of claim 1, wherein the treatment beams are applied to theretinal tissue to simultaneously create a plurality of spaced aparttreatment spots.